Four Corners hantavirus (FCV) is a newly discovered virus that causes chronic infection of the ubiquitous peridomestic rodent Peromyscus maniculatus, and the cause of the highly lethal hantavirus-associated respiratory distress syndrome (HARDS) in humans. Approximately 50% of HARDS cases in the United States have occurred within the state of New Mexico, and the University of New Mexico has become the referral center for many cases that occur outside of New Mexico. American Indian populations are by far the most heavily affected by the HARDS epidemic. Since early June 1993, when the association between FCV and HARDS was recognized, we have (1) developed a PCR-based diagnostic system for patients with possible FCV infection; (2) cloned and sequenced the great majority of the coding sequence for the structural antigens of the virus; (3) developed highly sensitive and specific serologic diagnosis for human and rodent IgM and IgG anti-FCV antibodies, based upon recombinant DNA from FCV and its relatives; and (4) begun preliminary rodent sero- surveillance with the new homologous antigens. We propose to: A. Use the newly developed recombinant antigen-derived serologic diagnostic methods to annually monitor seroprevalence of FCV and its relatives in small mammals at three sentinel sites within New Mexico. Correlate seroprevalence data with ecologic measurements and HARDS incidence. B. Test for correlations between ecological parameters such as habitat type, climatological conditions, biomass, and food source availability, and seroprevalence of FCV in rodents. C. Monitor genetic variation of FCV S segment and M segment by PCR in rodents and HARDS patients, to assess the annual rate of mutation and geographic variation among FCV and its relatives. D. Continue to refine and develop our understanding of the molecular structure and antigenicity of FCV, by cloning the remaining region of S segment and the entirety of L segment, and continuing our efforts to use the new clones to further refine the sensitivity and specificity of FCV serologic testing. We will map the dominant epitopes of FCV structural proteins for IgG and IgM antibodies. In collaboration we will develop monoclonal antibodies for direct detection and quantitation of FCV in the tissues and plasma of infected patients. The quantitative information derived from antigen assays will be examined for its predictive value for response to therapy and outcome.